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Purpose: To study the therapeutic effect of hemagglutinin-2 and fimbrial (HA2-FimA) vaccine on experimental periodontitis in rats. Materials and Methods: The first batch of rats was divided into two groups and immunised with pure water or pVAX1-HA2- FimA at the age of 6, 7, and 9 weeks. After sacrificing the animals, total RNA was extracted from the spleens for RNA high-throughput sequencing (RNA-Seq) analysis. The second batch of rats was divided into four groups (A, B, C, D), and an experimental periodontitis rat model was established by suturing silk thread around the maxillary second molars of rats in groups B, C, and D for 4 weeks. The rats were immunised with pure water, pVAX1-HA2-FimA vaccine, empty pVAX1 vector, and pure water at 10, 11, and 13 weeks of age, respectively. Secretory immunoglobulin A (SIgA) antibodies and cathelicidin antimicrobial peptide (CAMP) levels in saliva were measured by enzyme-linked immunosorbent assay (ELISA). All rats were euthanised at 17 weeks of age, and alveolar bone loss was examined using micro-computed tomography (Micro-CT). Results: Through sequencing analysis, six key genes, including Camp, were identified. Compared with the other three groups, the rats in the periodontitis+pVAX1-HA2-FimA vaccine group showed higher levels of SIgA and CAMP (p < 0.05). MicroCT results showed significantly less alveolar bone loss in the periodontitis+pVAX1-HA2-FimA vaccine group compared to the periodontitis+pVAX1 group and periodontitis+pure water group (p < 0.05). Conclusion: HA2-FimA DNA vaccine can increase the levels of SIgA and CAMP in the saliva of experimental periodontitis model rats and reduce alveolar bone loss. [ABSTRACT FROM AUTHOR]

AbstractThe ability of Candida albicans to switch among yeast, hyphal, and pseudohyphal forms underlies its adaptability and pathogenicity. While cAMP-dependent signaling has long been considered central to hyphal growth, recent multi-omics studies show that cAMP-independent mechanisms also drive morphological changes. Basal PKA activity, cyclin-dependent kinases (e.g., Cdc28), and other regulators can promote shape-shifting even without classical cAMP pathways. In addition, N-acetylglucosamine (GlcNAc) acts as a potent signal that induces hyphal growth independently of its metabolic role, directly connecting environmental cues to morphological states. By integrating transcriptomic, proteomic, and phosphoproteomic data, this review exposes the intricate networks controlling C. albicans morphogenesis. A clearer understanding of these complex regulatory circuits lays the groundwork for future studies that employ advanced multi-omics analyses. Such approaches will help elucidate how these pathways converge, how they respond to changing environments, and how they might be harnessed or disrupted to influence fungal behavior. [ABSTRACT FROM AUTHOR]

cGMP plays a central role in cardiovascular regulation in health and disease. It is synthesized by NO or natriuretic peptide activated cyclases and hydrolyzed to 5′GMP by select members of the PDEs (phosphodiesterase) superfamily. The primary downstream effector is cGMP-dependent protein kinase, primarily cGK-1a (cyclic GMP-dependent protein kinase 1 alpha) also known as protein kinase G 1a in the heart and vasculature. cGMP signaling is controlled in intracellular nanodomains to regulate myocyte growth, survival, metabolism, protein homeostasis, G-protein–coupled receptor signaling, and other critical functions. The vascular effects of cGMP signaling have been dominated by its lowering of smooth muscle tone, but other cellular processes are also engaged. Localization of cyclases and corresponding PDEs within intracellular domains, along with their varying expression across different cell types, adds multiorgan complexity to cGMP signaling. This diversity can be leveraged therapeutically by targeting selective pathway components to impact some but not other cGMP signaling effects. Here, we review the generation and regulation of cGMP by PDEs and cyclases, focusing mainly on their role in cardiac physiology and pathophysiology. Current therapeutic uses of cGMP modulation and ongoing trials testing new potential applications are discussed. [ABSTRACT FROM AUTHOR]

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which transmits circadian information to other brain regions and regulates the timing of sleep and wakefulness. Neurons in the lateral hypothalamus (LH), particularly those producing melanin-concentrating hormone (MCH) and orexin, are key regulators of sleep and wakefulness. Although the SCN receives nonphotic input from other brain regions, the mechanisms of functional input from the LH to the SCN remain poorly understood. Here, we show that orexin and MCH peptides influence the circadian period within the SCN of both sexes. When these neurons are ablated, the circadian behavioral rhythms are lengthened under constant darkness. Using anterograde and retrograde tracing, we found that orexin and MCH neurons project to the SCN. Furthermore, the application of these peptides to cultured SCN slices shortened circadian rhythms and reduced intracellular cAMP levels. Additionally, pharmacological reduction of intracellular cAMP levels similarly shortened the circadian period in SCN slices. These findings suggest that orexin and MCH peptides from the LH contribute to the modulation of the circadian period in the SCN. [ABSTRACT FROM AUTHOR]

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is dysfunctional in individuals with cystic fibrosis (CF). The permeability of CFTR can be experimentally manipulated though different mechanisms, including activation via inducing the phosphorylation of residues in the regulatory domain as well as altering the gating/open probability of the channel. Phosphorylation/activation of the channel is achieved by exposure to compounds that increase intracellular cAMP, with forskolin and IBMX commonly used for this purpose. Cact-A1 is a unique CFTR activator that does not increase intracellular cAMP, and VX-770 (ivacaftor) is a CFTR potentiator that is used experimentally and therapeutically to increase the open probability of the channel. Using primary human nasal epithelial cell (HNEC) cultures and Fischer rat thyroid (FRT) epithelial cells exogenously expressing functional CFTR, we examined the impact of VX-770, Cact-A1, and forskolin/IBMX on CFTR activity during analysis in an Ussing chamber. Relative contributions of these compounds to maximal CFTR activity were dependent on order of exposure, the presence of chemical and electrical gradients, the level of constitutive CFTR function, and the cell model tested. Increasing intracellular cAMP appeared to change cellular functions outside of CFTR activity that resulted in alterations in the drive for chloride through CFTR. These results demonstrate that one can utilize combinations of small-molecule CFTR activators and potentiators to provide detailed characterization of CFTR-mediated ion transport in primary HNECs and properties of these modulators in both primary HNECs and FRT cells. Future studies using these approaches may assist in the identification of novel defects in CFTR function and the identification of modulators with unique impacts on CFTR-mediated ion transport. [ABSTRACT FROM AUTHOR]

G protein-coupled receptor (GPCR) signalling pathways underlie numerous physiological processes, are implicated in many diseases and are major targets for therapeutics. There are more than 800 GPCRs, which together transduce a vast array of extracellular stimuli into a variety of intracellular signals via heterotrimeric G protein activation and multiple downstream effectors. A key challenge in cell biology research and the pharmaceutical industry is developing tools that enable the quantitative investigation of GPCR signalling pathways to gain mechanistic insights into the varied cellular functions and pharmacology of GPCRs. Recent progress in this area has been rapid and extensive. In this Review, we provide a critical overview of these new, state-of-the-art approaches to investigate GPCR signalling pathways. These include novel sensors, Forster or bioluminescence resonance energy transfer assays, libraries of tagged G proteins and transcriptional reporters. These approaches enable improved quantitative studies of different stages of GPCR signalling, including GPCR activation, G protein activation, second messenger (cAMP and Ca2+) signalling, p-arrestin recruitment and the internalisation and intracellular trafficking of GPCRs. [ABSTRACT FROM AUTHOR]

In 1781 William Thomas Beckford (1760–1844) inherited a vast colonial fortune built on West Indian sugar and slavery. To mark the occasion, his guardians commissioned a cantata from Venanzio Rauzzini (with words by Girolamo Tonioli) and enlisted the renowned castrati Gasparo Pacchierotti and Giusto Ferdinando Tenducci to perform it. More than a simple panegyric, Il tributo was a thinly veiled attempt at "straightening out" the young man's perceived effeminacy and his apathy over the business of empire, qualities that were all the more problematic in light of his white West Indian ancestry. The performance of Il tributo, I argue, was a critical moment of social initiation in which cultural norms and structures relating to English masculinity were reinforced and ultimately destabilized. This article unravels the threads between Beckford's auditory intimacy with the castrato voice and his tenuous hold on the signifiers of Englishness. It takes Il tributo as the point of departure for exploring voice, race, and empire in late eighteenth-century Britain, imagining Beckford's experience of listening to Il tributo as a practice of Camp, through which he sought to negotiate his place within the British Empire. "Camp" here refers to the sensibility glossed by Susan Sontag in 1964 as a quality of failed seriousness under extravagant circumstances, though its roots are bound up with eighteenth-century Britain's global-colonial ambitions. What I term "Camp aurality" was the result of Beckford's fixation with the castrato voice, or melophilia, and had the power to dethrone the cantata's moral seriousness. While the performance of Il tributo ultimately failed to enforce imperial proscriptions regarding race and sex, it remains an ambivalent but instructive sonic artifact of the British planter class at the summit of its power. [ABSTRACT FROM AUTHOR]

Fluorescence resonance energy transfer (FRET)‐based biosensors are powerful tools for studying second messengers with high temporal and spatial resolution. FRET is commonly detected by ratio imaging, but fluorescence lifetime imaging microscopy (FLIM), which measures the donor fluorophore's lifetime, offers a robust and more quantitative alternative. We have introduced and optimized four generations of FRET sensors for cAMP, based on the effector molecule Epac1, including variants for either ratio imaging or FLIM detection. Recently, Massengill and colleagues introduced additional mutations that improve cytosolic localization in these sensors, focusing on constructs optimized for ratio imaging. Here we present and briefly characterize these mutations in our dedicated FLIM sensors, finding they enhance cytosolic localization while maintaining performance comparable to original constructs. [ABSTRACT FROM AUTHOR]

Brain astrocyte glycogenolysis is regulated in part by the second messenger adenosine 3′5′‐cyclic monophosphate (cAMP). Hypothalamic astrocyte glycogen metabolism shapes glucose counterregulation, under the control of glucose transporter‐2 (GLUT2), a plasma membrane glucose carrier and sensor. Hypothalamic astrocyte cAMP is subject to neurotransmitter control, but effects of nutrient cues on this messenger are unclear. Here, an established hypothalamic primary astrocyte culture model and gene knockdown tools were used to investigate the premise that GLUT2 exerts sex‐dimorphic regulation of cAMP‐protein kinase A (PKA) signalling in these glia. Data show that basal cAMP was elevated in female versus male; GLUT2 gene silencing up‐regulated or down‐regulated this profile in male versus female. Glucoprivation increased cAMP content in astrocytes of each sex, yet GLUT2 siRNA pretreatment exacerbated (male) or blunted (female) this stimulatory effect. PKA and phosphoPKA levels in glucose‐supplied astrocytes were increased (male) or decreased (female) by GLUT2 knockdown. PKA protein was amplified, yet phosphoPKA was refractory to glucose withdrawal in male, while females showed sustained PKA expression alongside diminished phosphoPKA. GLUT2 siRNA pretreatment exacerbated glucoprivic augmentation of PKA content in male but down‐regulated both PKA and phosphoPKA proteins in female. Evidence for parallel GLUT2 siRNA‐associated changes in cAMP and PKA, albeit in opposing directions in the two sexes, infers that GLUT2 control of hypothalamic astrocyte cAMP‐dependent PKA signalling is sex‐specific. Data also disclose that in the female, GLUT2 curbs the baseline phosphoPKA/PKA expression ratio but is not involved in glucoprivic suppression of this ratio. [ABSTRACT FROM AUTHOR]

Artisanal and small-scale gold mining (MAPEOs) are considered to be one of the main sources of mercury release into the environment. Considering the gold mining activities, this study evaluated the Hg concentration in 27 apiaries (Apis spp.) in the South of the Legal Amazon, Mato Grosso State, Brazil. A total of 243 samples distributed in 81 samples of bees, 81 beeswax, and 81 of honeys, collected between the months of July and November 2022, were analyzed. One bee sample showed Hg concentration above the limit of quantification (68.8 ng g−1), 27 samples were between the limit of detection and limit of quantification (15 samples of bees, 8 of wax and 4 of honey). In all study areas, trace levels of Hg concentration were detected, 12 near MAPEOs areas and 16 near crop areas. It recorded that the honeys analyzed in this study in Mato Grosso are not contaminated by Hg, not offering any risk to consumers of the product. It is noteworthy that the use of bioindicator tools such as bees, beeswax, and honey is effective in relation to Hg monitoring in apiaries. It can also infer that the implementation of beekeeping in areas that will go through experience the process of environmental recovery, after the mining exploitation, is feasible, in line with permanent biomonitoring of the region. [ABSTRACT FROM AUTHOR]

Background: Semen Cuscutae flavonoids (SCFs) constitute a class of metabolites of Semen Cuscutae, a botanical drug that was recently found to have an anti-depression effect. This study aimed to evaluate the anti-depression effects of SCFs in chronic unpredictable mild stress (CUMS)-induced mice and to interrogate the underlying mechanisms. Materials and methods: The CUMS mice were used for assessing the effects of SCFs treatments on depression. Mice were randomly divided into five groups. Four groups were subjected to the CUMS induction and concomitantly administered orally with either the vehicle or with a high-, medium-, and low-dose of SCFs, once per day for 4 weeks. One group was kept untreated as a control. The mice were then assessed for their statuses of a number of depression-related parameters, including body weight, food intake, sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swim test (FST). In addition, a day after the completion of these tests, biopsies from the hippocampus were harvested and used to perform metabolomics by HPLC-MS/MS and to assess the levels of cAMP by ELISA and the levels of PKA, CREB, p-CREB, and BDNF by Western blot analyses. Results: SCFs resulted in significant increases in both body weight and food intake and in the amelioration of the depressive-like behaviors in CUMS mice. A high-dose SCFs treatment led to significant alterations in 72 metabolites, of which 26 were identified as potential biomarkers for the SCFs treatment. These metabolites are associated with lipid, amino acid, and nucleotide metabolism. Among 26 metabolites, cAMP was positively correlated with body weight, SPT, OFT-total distance, and OFT-central residence time, while negatively correlated with immobility time in TST and FST, linking a change in cAMP with the SCFs treatment and the significant improvement in depressive symptoms in CUMS mice. Further analyses revealed that the levels of cAMP, PKA, CREB, p-CREB, and BDNF were reduced in the hippocampus of CUMS mice but were all increased following the SCFs treatments. Conclusion: SCFs could ameliorate hippocampal metabolic disturbances and depressive behaviors and cause the activation of the cAMP-PKA-CREB-BDNF signaling pathway in the hippocampus of CUMS mice. [ABSTRACT FROM AUTHOR]

Tendons, which transmit force from muscles to bones, are highly prone to injury. Understanding the mechanisms driving tendon fate would impact efforts to improve tendon healing, yet this knowledge is limited. To find direct regulators of tendon progenitor emergence, we performed a zebrafish high-throughput chemical screen. We established forskolin as a tenogenic inducer across vertebrates, functioning through Creb1a, which is required and sufficient for tendon fate. Putative enhancers containing cyclic AMP (cAMP) response elements (CREs) in humans, mice, and fish drove specific expression in zebrafish cranial and fin tendons. Analysis of these genomic regions identified motifs for early B cell factor (Ebf/EBF) transcription factors. Mutation of CRE or Ebf/EBF motifs significantly disrupted enhancer activity and specificity in tendons. Zebrafish ebf1a/ebf3a mutants displayed defects in tendon formation. Notably, Creb1a/CREB1 and Ebf1a/Ebf3a/EBF1 overexpression facilitated tenogenic induction in zebrafish and human pluripotent stem cells. Together, our work identifies the functional conservation of two transcription factors in promoting tendon fate. [Display omitted] • Chemical screen identifies the cAMP-PKA-Creb1/CREB1 pathway as promoting tendon fate • Creb1a induces tendon fate by directly activating the newly identified scxa enhancer SEN • Motif analysis of enhancer regions identifies Ebf/EBF as a novel tendon regulator • Creb1/CREB1 and Ebf/EBF are sufficient and necessary for tendon development From a zebrafish chemical screen to mammalian stem cell culture, Niu et al. demonstrate that forskolin promotes tendon fate across vertebrate species through the cyclic AMP-PKA-Creb1/CREB1 axis. The induction involves previously unidentified zebrafish and putative human enhancers, which led to the discovery of the tendon-inducing functions of Ebf/EBF transcription factors. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are related intestinal L-cell derived secretory products. GLP-1 has been extensively studied in terms of its influence on metabolism, but less attention has been devoted to GLP-2 in this regard. The current study compares the effects of these proglucagon-derived peptides on pancreatic beta-cell function, as well as on glucose tolerance and appetite. The insulin secretory effects of GLP-1 and GLP-2 (10−12–10−6 M) were investigated in BRIN-BD11 beta-cells as well as isolated mouse islets, with the impact of test peptides (10 nM) on real-time cytosolic cAMP levels further evaluated in mouse islets. The impact of both peptides (10−8–10−6 M) on beta-cell growth and survival was also studied in BRIN BD11 cells. Acute in vivo (peptides administered at 25 nmol/kg) glucose homeostatic and appetite suppressive actions were then examined in healthy mice. GLP-1, but not GLP-2, concentration dependently augmented insulin secretion from BRIN-BD11 cells, with similar observations made in isolated murine islets. In addition, GLP-1 substantially increased [cAMP]cyt in islet cells and was significantly more prominent than GLP-2 in this regard. Both GLP-1 and GLP-2 promoted beta-cell proliferation and protected against cytokine-induced apoptosis. In overnight fasted healthy mice, as well as mice trained to eat for 3 h per day, the administration of GLP-1 or GLP-2 suppressed appetite. When injected conjointly with glucose, both peptides improved glucose disposal, which was associated with enhanced glucose-stimulated insulin secretion by GLP-1, but not GLP-2. To conclude, the impact of GLP-1 and GLP-2 on insulin secretion is divergent, but the effects of beta-cell signaling and overall health are similar. Moreover, the peripheral administration of either hormone in rodents results in comparable positive effects on blood glucose levels and appetite. [ABSTRACT FROM AUTHOR]

This paper intends to explore the convergence of queerness and blackness in Paul Mendez's Rainbow Milk and black portraiture art, especially Kehinde Wiley's portraits, with particular attention to his Christ-related works. With this purpose, I will review the narratives of post-blackness and black camp (Pochmara and Wierzchowska 2017) characteristic of Bertram D. Ashe's post-Soul aesthetics. Unlike the monolithic discourses of the Civil Rights generation, these artists cross over conceptions of race, sexuality and privilege in intersectional terms. They break with racial authenticity and play with appropriation, irony and camp to renegotiate and articulate othernesses and render them grievable. [ABSTRACT FROM AUTHOR]

Objective: To analyze expression and models of CD39, CTLA-4, and PD-1 on T cells, to investigate effect of cyclic adenosine monophosphate (cAMP) on their expressions, and to analyze key pathways regulating their expressions. Methods: Small molecules such as adenylate cyclase (ACs) activators, phosphodiesterase(PDE) inhibitors, protein kinase A(PKA) inhibitors and PKA-CREB inhibitors were used to stimulate rhesus macaque peripheral blood mononuclear cells in vitro, and changes in ratios of CD39, CTLA-4, and PD-1 positive (CD39+, CTLA-4+, and PD-1+) T cells were detected by flow cytometry, and to analyze their expression patterns, and effects of small molecules on ratio of positively expressing/co-expressing cells were compared to clarify expression patterns and molecules and pathways that regulated expression. Results: Normal macaque CD4+T and CD8+T cells had low ratios of CD39+, CTLA-4+, and PD-1+ cells, and positive cells predominantly expressed only one of these molecules. Increasing intracellular cAMP levels did not affect CD39+T cell ratio, significantly increased CTLA-4+T cell ratio, and decreased PD-1+CD8+T cell ratio, involving cell populations with mono expression of CTLA-4 and PD-1. Inhibition of PKA activity reduced potentiation of CTLA-4 expression by broad-spectrum PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX), but did not affect PD-1 expression. Exchange protein activated by cAMP did not affect CTLA-4 expression but downregulate PD-1+CD4+/CD8+T cells ratio. Upregulation of CTLA-4 by PDE4B selective inhibitors was similar to IBMX, while regulation of PDE3 and PDE5A selective inhibitors on PD-1 expression wassimilar to IBMX. Conclusion: CD39, CTLA-4 and PD-1 have different expression models on T cells but are differentially regulated by cAMP levels and have different cAMP downstream signal pathways involved in expression regulation. [ABSTRACT FROM AUTHOR]

Background and Purpose: The PDE4 family is considered a prime target for therapeutic intervention in several fibro‐inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor. Experimental Approach: In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high‐resolution computed tomography scan/AI‐Ashcroft score), whole‐lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next‐generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter‐regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease‐relevant in vitro assay of IPF. Key Results: Nerandomilast improved the decline of lung function parameters in bleomycin‐treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single‐cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease‐related (bio)markers were inhibited by nerandomilast in a concentration‐dependent manner. Conclusions and Implications: This study further supports the available knowledge about the anti‐inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis. [ABSTRACT FROM AUTHOR]

The gamma-ray-induced random mutagenesis of an engineered β-carotene-producing Escherichia coli XL1-Blue resulted in the variant Ajou 45, which exhibits significantly enhanced β-carotene production. The whole-genome sequencing of Ajou 45 identified 55 mutations, notably including a reduction in the copy number of cyaA, encoding adenylate cyclase, a key enzyme regulating intracellular cyclic AMP (cAMP) levels. While the parental XL1-Blue strain harbors two copies of cyaA, Ajou 45 retains only one, potentially leading to reduced intracellular cAMP concentrations. This reduction may alleviate catabolite repression and redirect metabolic flux toward the β-carotene biosynthesis pathway. To validate this mechanistic insight, a targeted cyaA knockout was engineered in XL1-Blue, and its β-carotene production and growth phenotypes were compared with those of Ajou 45 and XL1-Blue. The findings demonstrated that a reduced cyaA copy number substantially enhances β-carotene biosynthesis by modulating cAMP-mediated regulatory networks. This study highlights the efficacy of integrating random mutagenesis with integrative genomic analysis for microbial strain engineering and presents a novel strategy for enhancing carotenoid production in E. coli. [ABSTRACT FROM AUTHOR]

Queer subjectivity invites discussions around gender performativity, culture, narratives of "coming out," and identity politics. Postcolonial queer subjects—like those emerging from the Philippines—require additional layers of critique attending to language, practice, and resistance. This brief reflection will explore the place of camp, rampa, and posthuman worldviews in the constitution of Filipino queer bodies. It argues that as queer narratives become global—and normalized— camp and rampa offer a place where queerness can both expand critical theology and imaginations of the human. [ABSTRACT FROM AUTHOR]

We studied the level of immunocompetent blood cells, phagocytic activity of neutrophils, concentrations of cytokines, circulating immune complexes and levels of cyclic nucleotides (cAMP and cGMP) in blood serum with different levels of soluble adhesion molecules NCAM (CD56) and immunoglobulin Fc-receptor III (CD16) in nearly healthy people living in the Arctic territory. An increase in serum concentrations of sCD56 and sCD16 in nearly healthy adults of working age was found to be associated with an increase in the level of cells bearing the corresponding membrane receptors. An increase in sCD56 concentrations was accompanied by an increase in the level of NK (CD3-CD16+CD56+) and T-NK cells (CD3+CD16+CD56+), whereas an increase in sCD16 level, by a decrease in the counts of lymphocytes circulating in blood, mainly, T-helper cells (CD3+CD4+), cytotoxic T-lymphocytes (CD3+CD8+), and activated T-lymphocytes (CD3+HLADR+). Elevated sCD56 concentrations were associated with the increased levels of pro-inflammatory IL-1β, IL-6, TNF-α, and anti-inflammatory IL-10 cells. Concentrations of circulating immune complexes rose with increasing sCD16 and sCD56 levels. The signal conduction activity grew with increasing concentrations of CD16+ and CD56+ leukocytes of peripheral blood and sCD56+ leukocytes, and the shedding of these molecules occurred against the background of cAMP and cGMP decreasing concentrations. [ABSTRACT FROM AUTHOR]

Adrenergic receptors (ARs) are preferentially expressed by innate lymphocytes such as natural killer (NK) cells. Here, we study the effect of epinephrine‐mediated stimulation of the β2‐adrenergic receptor (β2AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA‐1. This reduced the adhesion of NK cells to ICAM‐1, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP‐protein kinase A (PKA) pathway. Repeated exposure to β2AR agonists resulted in the desensitization of the β2AR via a PKA feedback loop‐initiated G‐protein switch. Therefore, acute epinephrine stimulation of chronically β2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA‐1 activity. Sustained stimulation by long‐acting β2‐agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the β2AR. However, peripheral NK cells from LABA‐treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells. [ABSTRACT FROM AUTHOR]

Objective: To quantify race, sex, comorbidities, Medicaid status, and compare health outcomes for Medicare-only versus Medicare/Medicaid dual-enrolees who developed a hard-to-heal venous leg ulcer (VLU). Method: Medicare Limited Data Standard analytic hospital inpatient and outpatient department files were used to follow episodes of medical care for a VLU from 1 October 2015–2 October 2019. In an earlier study, patients diagnosed concurrently with chronic venous insufficiency and a VLU were propensity-matched. In this current work, cohorts were split into patients enrolled in Medicare-only and those enrolled in Medicare and Medicaid (dual-enrolees). Treatment methods were compared and the most commonly used cellular, acellular and matrix-like product (CAMP) among Medicare beneficiaries—dehydrated human amnion chorion membrane (DHACM)—was evaluated. Episode claims were used to document demographics, comorbidities and treatments of Medicare enrolees who developed VLUs and outcomes such as time to ulcer closure, rates of complications and hospital usage rates. Quality of life (QoL) metrics, such as pain and time to VLU closure, were compared across the groups. Results: Of the 555,284 Medicare beneficiaries evaluated in this analysis, 27% were Medicare/Medicaid dual-enrolees and 73% were Medicare-only enrolees. To qualify for Medicaid, patient income had to be ≤133% of the federal poverty level. Only 3% of Medicare-only patients and 6% of dual-enrolees had an Advantage plan, a lower rate than the general Medicare population. Dual-enrolees, compared to those covered by Medicare-only, demonstrated: a Charlson Comorbidity Index (CCI) score one point greater (p<0.0001); a higher percentage (16%) of patients from minority ethnic backgrounds; and significantly higher rates of emergency department visits (p<0.0001) and cellulitis (p=0.034). Dual-enrolees who received early and regularly applied CAMPs also reduced their treatment time by 21 days (p=0.0027), all of which can impact costs. Conclusion: The socioeconomic status of dual-enrolees included near poverty status, a higher percentage of patients from a minority ethnic background, and high rates of comorbidities compared to their Medicare-only counterparts. The VLUs of dual-enrolees took longer to close, developed more complications, and used significantly more hospital resources and expenses. Outcomes significantly improved when VLU episodes were treated with a CAMP, such as DHACM, while following parameters for use. Socioeconomic variables are associated with poor outcomes for patients with hard-to-heal (chronic) wounds. This should be tracked to find cost-effective interventions throughout their journey to provide equitable care and ensure they are not left behind. Greater access for dual-enrolees to CAMPs has the potential to improve clinical outcomes and patient QoL, while concomitantly reducing overall healthcare expenditure. [ABSTRACT FROM AUTHOR]

Background and Aim: The prevalence of alcohol use in India is ranged from 3.8% to 65.8%. One in every five alcohol users needs treatment. Lack of knowledge about the ill effects of alcohol and an 83% of treatment gap increase the risk. Among many available strategies, community-based alcohol de-addiction camps (ADCs) can offer support to alcohol users. This study aims to assess the participants’ sociodemographic characteristics and alcohol use patterns in alcohol users attending an ADC. Materials and Methods: This cross-sectional descriptive study was conducted at ADC in September 2022. Data from 58 participants were collected using a sociodemographic and clinical data sheet and the alcohol use disorder identification test. Results: The majority of participants voluntarily attended the camp and were aged between 25 and 45 years (67.2%). Most were married (79.3%), had completed secondary education (34.5%), worked as farmers (36.3%), and had a monthly income of INR 6000–18,000 (56.9%). Regarding alcohol use patterns, the majority were daily users (84.5%) for over 5 years (51.7%) and had severe alcohol dependence (86.2%). More than half of the participants had a previous attempt to quit (58.6%) and cited family (51.72%) as a primary reason, followed by health and social respect (48.24%) to quit alcohol. Conclusions: Men aged

In this review, we explore the potential of cAMP-Phosphodiesterase 4 (PDE4), a key intracellular enzyme, as a therapeutic target for cancer treatment. cAMP-PDEs play a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP), an essential second messenger involved in cell proliferation and metastasis in a tissue-specific manner depending on the PDE isoforms present. Elevated PDE4 expression has been reported in cancers such as breast, cervical, and lung cancer. Specific PDE4 subtypes are recognized for their roles in cancer progression, making PDE4 inhibitors promising candidates for therapeutic intervention. This review examines the role of PDE4 in cancer progression and highlights the therapeutic potential of studied PDE4 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Aquaporin 2 (AQP2) contributes to water reabsorption and urine concentration by migrating to the luminal surface of the collecting ducts in an anti-diuretic hormone-stimulated manner, and the signaling pathway involved in AQP2 subcellular localization is a target for arginine vasopressin receptor antagonists (aquaretics). This study investigated the involvement of AQP2 in the diuretic effect and mechanisms of Goreisan (GRS), a traditional Japanese Kampo medicine used to treat conditions such as edema in patients with decreased urination. GRS exerted diuretic effects on desmopressin (DDAVP)-induced decreases in urine output and the level of AQP2 phosphorylated at Serine269 (pSer269-AQP2) in the renal tissues of mice. Furthermore, GRS inhibited the accumulation of pSer269-AQP2 to the luminal side following forskolin stimulation using a 3D culture model of the kidney collecting duct cell line mIMCD-3. GRS induced a transient increase in the intracellular Ca2+ concentration via the calcium-sensing receptor (CaSR) and suppressed the forskolin-stimulated increase in cAMP production. These results suggest that GRS regulates urine volume by modulating the subcellular localization of AQP2 via CaSR.

Children with lived cancer experience encounter adversity, therefore experiences promoting psychosocial health are necessary. This pilot study determined the impact of recreational oncology camps (ROC) on resilience, hope, social support, and mental well-being in youth who have lived with cancer. Youth (6–18 years) with cancer experience enrolled in an 11-day session of ROC (Muskoka, Ontario, Canada) were invited to participate. Participants completed a survey [Children’s Hope Scale (CHS), Child and Youth Resilience Measure (CYRM-R), Social Provisions Scale (SPS-5), and Short Warwick–Edinburgh Mental Wellbeing Scale (SWEMWBS)] on the first (T1) and last day (T2) of camp, and 3 months post-camp (T3). Repeated-measures ANOVAs evaluated differences in survey scores among time points. Ten participants (14.1 ± 2.5 years) were included in the analysis. CHS scores at T3 were lower than T1 and T2 (F = 9.388, p = 0.008). CYRM-R, SPS-5, and SWEMWBS scores were high but did not differ between time points. Hope decreased 3 months post-camp, suggesting a need for continued psychosocial support. Overall, the ROC environment is associated with positive psychosocial health.

Drawing empirical insights from NGOs working on statelessness, repatriation and children’s rights relating to children residing in al-Hol and Roj camps in North-East Syria, I explore critiques of UK government decision-making concerning repatriation amid unprecedented use of citizenship deprivation powers affecting ISIS-associated children which has enforced parent-child separation. A policy gap is created where children are unable to be returned with caregivers if citizenship is deprived. Adoption of a case-by-case approach rather than coherent policy response to repatriation prolongs children’s detainment within insecure camps. Using a critical race lens, I advance theoretical understanding of spatio-temporal logics of (in)securitisation within the context of counter-terrorism policies affecting British children in NES camps through convergence of violent conflict, citizenship deprivation and state failure to repatriate. A children’s right approach to repatriation decision-making is required to ensure British children’s safe return and right to family. [ABSTRACT FROM AUTHOR]

In a crisis‐shaken globalised world, migration‐related sites of detention emerge as a harmful figure of attempts to contain human mobility. The new Closed Controlled Access Centre (CCAC) on Samos is a blueprint for the EU's future border practices. While openly dehumanising conditions contributed to the previous “old camp” amounting to a torturing environment, the new remote and securitised CCAC promised safety and humanitarian care. Psycho‐geographical counter‐mappings by people living in the camps and of human rights defenders allow the reading of the hotspot camps as a built environment and social space. They expose how the violent neglect of the old camp transforms into the surveilled and weaponised space of yet another torturing environment. This time, it operates a necropolitical space of uncare that distributes harm differentially. The findings emphasise the abolitionist argument that camps cannot be turned into “better” places. [ABSTRACT FROM AUTHOR]